Selective androgen receptor modulators and methods of use thereof

ABSTRACT

This invention provides a class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; and/or g) decreasing the incidence of, halting or causing a regression of prostate cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This Application is a Continuation-in-Part Application of U.S.Ser. No. 09/935,044, filed Aug. 23, 2001 and of U.S. Ser. No.09/935,045, filed Aug. 23, 2001, which are Continuation-in-PartApplications of U.S. Ser. No. 09/644,970 filed Aug. 24, 2000; and claimspriority of U.S. Ser. No. 60/300,083, filed Jun 25, 2001, which arehereby incorporated by reference.

GOVERNMENT INTEREST STATEMENT

[0002] This invention was made in whole or in part with governmentsupport under grant number R29 CA068096 awarded by the National CancerInstitute, National Institute of Health, and under grant number R15HD35329, awarded by the National Institute of Child Health and HumanDevelopment, National Institute of Health. The government may havecertain rights in the invention.

FIELD OF INVENTION

[0003] The present invention relates to a novel class of androgenreceptor targeting agents (ARTA), which demonstrate androgenic andanabolic activity of a nonsteroidal ligand for the androgen receptor.The agents define a new subclass of compounds, which are selectiveandrogen receptor modulators (SARMs) useful for a) male contraception;b) treatment of a variety of hormone-related conditions, for exampleconditions associated with Androgen Decline in Aging Male (ADAM); c)treatment of conditions associated with Androgen Decline in Female(ADIF); d) treatment and/or prevention of acute and/or chronic muscularwasting conditions; e) preventing and/or treating dry eye conditions; f)oral androgen replacement therapy; and/or g) decreasing the incidenceof, halting or causing a regression of prostate cancer.

BACKGROUND OF THE INVENTION

[0004] The androgen receptor (“AR”) is a ligand-activatedtranscriptional regulatory protein that mediates induction of malesexual development and function through its activity with endogenousandrogens. Androgens are generally known as the male sex hormones. Theandrogenic hormones are steroids which are produced in the body by thetestes and the cortex of the adrenal gland or can be synthesized in thelaboratory. Androgenic steroids play an important role in manyphysiologic processes, including the development and maintenance of malesexual characteristics such as muscle and bone mass, prostate growth,spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol. Met.Clin. N. Am. 23:857-75 (1994)). The endogenous steroidal androgensinclude testosterone and dihydrotestosterone (“DHT”). Testosterone isthe principal steroid secreted by the testes and is the primarycirculating androgen found in the plasma of males. Testosterone isconverted to DHT by the enzyme 5 alpha-reductase in many peripheraltissues. DHT is thus thought to serve as the intracellular mediator formost androgen actions (Zhou, et al., Molec. Endocrinol. 9:208-18(1995)). Other steroidal androgens include esters of testosterone, suchas the cypionate, propionate, phenylpropionate, cyclopentylpropionate,isocarporate, enanthate, and decanoate esters, and other syntheticandrogens such as 7-Methyl-Nortestosterone (“MENT’) and its acetateester (Sundaram et al., “7 Alpha-Methyl-Nortestosterone(MENT): TheOptimal Androgen For Male Contraception,” Aim. Med., 25:199-205 (1993)(“Sundaram”)). Because the AR is involved in male sexual development andfunction, the AR is a likely target for effecting male contraception orother forms of hormone replacement therapy.

[0005] Worldwide population growth and social awareness of familyplanning have stimulated a great deal of research in contraception.Contraception is a difficult subject under any circumstance. It isfraught with cultural and social stigma, religious implications, and,most certainly, significant health concerns. This situation is onlyexacerbated when the subject focuses on male contraception. Despite theavailability of suitable contraceptive devices, historically, societyhas looked to women to be responsible for contraceptive decisions andtheir consequences. Although concern over sexually transmitted diseaseshas made men more aware of the need to develop safe and responsiblesexual habits, women still often bear the brunt of contraceptive choice.Women have a number of choices, from temporary mechanical devices suchas sponges and diaphragms to temporary chemical devices such asspermicides. Women also have at their disposal more permanent options,such as physical devices including IUDs and cervical caps as well asmore permanent chemical treatments such as birth control pills andsubcutaneous implants. However, to date, the only options available formen include the use of condoms and vasectomy. Condom use, however is notfavored by many men because of the reduced sexual sensitivity, theinterruption in sexual spontaneity, and the significant possibility ofpregnancy caused by breakage or misuse. Vasectomies are also notfavored. If more convenient methods of birth control were available tomen, particularly long-term methods which require no preparativeactivity immediately prior to a sexual act, such methods couldsignificantly increase the likelihood that men would take moreresponsibility for contraception.

[0006] Administration of the male sex steroids (e.g., testosterone andits derivatives) has shown particular promise in this regard due to thecombined gonadotropin-suppressing and androgen-substituting propertiesof these compounds (Steinberger et al., “Effect of ChronicAdministration of Testosterone Enanthate on Sperm Production and PlasmaTestosterone, Follicle Stimulating Hormone, and Luteinizing HormoneLevels: A Preliminary Evaluation of a Possible Male Contraceptive,Fertility and Sterility 28:1320-28 (1977)). Chronic administration ofhigh doses of testosterone completely abolishes sperm production(azoospermia) or reduces it to a very low level (oligospermia). Thedegree of spermatogenic suppression necessary to produce infertility isnot precisely known. However, a recent report by the World HealthOrganization showed that weekly intramuscular injections of testosteroneenanthate result in azoospermia or severe oligospermia (i.e., less than3 million sperm per ml) and infertility in 98% of men receiving therapy(World Health Organization Task Force on Methods And Regulation of MaleFertility, “Contraceptive Efficacy of Testosterone-Induced Azoospermiaand Oligospermia in Normal Men,” Fertility and Sterility 65:821-29(1996)).

[0007] A variety of testosterone esters have been developed which aremore slowly absorbed after intramuscular injection and thus result ingreater androgenic effect. Testosterone enanthate is the most widelyused of these esters. While testosterone enanthate has been valuable interms of establishing the feasibility of hormonal agents for malecontraception, it has several drawbacks, including the need for weeklyinjections and the presence of supraphysiologic peak levels oftestosterone immediately following intramuscular injection (Wu, “Effectsof Testosterone Enanthate in Normal Men: Experience From a MulticenterContraceptive Efficacy Study,” Fertility and Sterility 65:626-36(1996)).

[0008] Steroidal ligands which bind the AR and act as androgens (e.g.testosterone enanthate) or as antiandrogens (e.g. cyproterone acetate)have been known for many years and are used clinically (Wu 1988).Although nonsteroidal antiandrogens are in clinical use forhormone-dependent prostate cancer, nonsteroidal androgens have not beenreported. For this reason, research on male contraceptives has focusedsolely on steroidal compounds.

[0009] Prostate cancer is one of the most frequently occurring cancersamong men in the United States, with hundreds of thousands of new casesdiagnosed each year. Unfortunately, over sixty percent of newlydiagnosed cases of prostate cancer are found to be pathologicallyadvanced, with no cure and a dismal prognosis. One approach to thisproblem is to find prostate cancer earlier through screening programsand thereby reduce the number of advanced prostate cancer patients.Another strategy, however, is to develop drugs to prevent prostatecancer. One third of all men over 50 years of age have a latent form ofprostate cancer that may be activated into the life-threatening clinicalprostate cancer form. The frequency of latent prostatic tumors has beenshown to increase substantially with each decade of life from the 50s(5.3-14%) to the 90s (40-80%). The number of people with latent prostatecancer is the same across all cultures, ethnic groups, and races, yetthe frequency of clinically aggressive cancer is markedly different.This suggests that environmental factors may play a role in activatinglatent prostate cancer. Thus, the development of treatment andpreventative strategies against prostate cancer may have the greatestoverall impact both medically and economically against prostate cancer.

[0010] Osteoporosis is a systemic skeletal disease, characterized by lowbone mass and deterioration of bone tissue, with a consequent increasein bone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being incapacitated. The elderly are atgreatest risk of osteoporosis, and the problem is therefore predicted toincrease significantly with the aging of the population. Worldwidefracture incidence is forecasted to increase three-fold over the next 60years, and one study estimated that there will be 4.5 million hipfractures worldwide in 2050.

[0011] Women are at greater risk of osteoporosis than men. Womenexperience a sharp acceleration of bone loss during the five yearsfollowing menopause. Other factors that increase the risk includesmoking, alcohol abuse, a sedentary lifestyle and low calcium intake.However, osteoporosis also occurs frequently in males. It is wellestablished that the bone mineral density of males decrease with age.Decreased amounts of bone mineral content and density correlates withdecreased bone strength, and predisposes to fracture. The molecularmechanisms underlying the pleiotropic effects of sex-hormones innon-reproductive tissues are only beginning to be understood, but it isclear that physiologic concentrations of androgens and estrogens play animportant role in maintaining bone homeostasis throughout thelife-cycle. Consequently, when androgen or estrogen deprivation occursthere is a resultant increase in the rate of bone remodeling that tiltsthe balance of resorption and formation to the favor of resorption thatcontributes to the overall loss of bone mass. In males, the naturaldecline in sex-hormones at maturity (direct decline in androgens as wellas lower levels of estrogens derived from peripheral aromatization ofandrogens) is associated with the frailty of bones. This effect is alsoobserved in males who have been castrated.

[0012] Androgen decline in the aging male (ADAM) refers to a progressivedecrease in androgen production, common in males after middle age. Thesyndrome is characterized by alterations in the physical andintellectual domains that correlate with and can be corrected bymanipulation of the androgen milieu. ADAM is characterized biochemicallyby a decrease not only in serum androgen, but also in other hormones,such as growth hormone, melatonin and dehydroepiandrosterone. Clinicalmanifestations include fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, obesity, sarcopenia, osteopenia, benign prostate hyperplasia,anemia, alterations in mood and cognition and prostate cancer.

[0013] Androgen Deficiency in Female (ADIF) refers to a variety ofhormone-related conditions including, common in females after middleagest. The syndrome is characterized by sexual dysfunction, decreasedsexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis,alterations in cognition and mood, anemia, depression, anemia, hairloss, obesity, endometriosis, breast cancer, uterine cancer and ovariancancer.

[0014] Muscle wasting refers to the progressive loss of muscle massand/or to the progressive weakening and degeneration of muscles,including the skeletal or voluntary muscles, which control movement,cardiac muscles, which control the heart (cardiomyopathics), and smoothmuscles. Chronic muscle wasting is a chronic condition (i.e. persistingover a long period of time) characterized by progressive loss of musclemass, weakening and degeneration of muscle. The loss of muscle mass thatoccurs during muscle wasting can be characterized by a muscle proteinbreakdown or degradation. Protein degradation occurs because of anunusually high rate of protein degradation, an unusually low rate ofprotein synthesis, or a combination of both. Protein degradation,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. Muscle wasting is associated with chronic, neurological,genetic or infectious pathologies, diseases, illnesses or conditions.These include Muscular Dystrophies such as Duchenne Muscular Dystrophyand Myotonic Dystrophy; Muscle Atrophies such as Post-Polio MuscleAtrophy (PPMA); Cachexias such as Cardiac Cachexia, AIDS Cachexia andCancer Cachexia, malnutrition, Leprosy, Diabetes, Renal Disease, ChronicObstructive Pulmonary Disease (COPD), Cancer, end stage Renal failure,Emphysema, Osteomalacia, HIV Infection, AIDS, and Cardiomyopathy, Inaddition, other circumstances and conditions are linked to and can causemuscle wasting. These include chronic lower back pain, advanced age,central nervous system (CNS) injury, peripheral nerve injury, spinalcord injury, chemical injury, central nervous system (CNS) damage,peripheral nerve damage, spinal cord damage, chemical damage, burns,disuse deconditioning that occurs when a limb is immobilized, long termhospitalization due to illness or injury, and alcoholism. Musclewasting, if left unabated, can have dire health consequences. Forexample, the changes that occur during muscle wasting can lead to aweakened physical state that is detrimental to an individual's health,resulting in increased susceptibility to infection, poor performancestatus and susceptibility to injury.

[0015] New innovative approaches are urgently needed at both the basicscience and clinical levels to develop compounds which are useful for a)male contraception; b) treatment of a variety of hormone-relatedconditions, for example conditions associated with Androgen Decline inAging Male (ADAM), such as fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benignprostate hyperplasia, alterations in mood and cognition and prostatecancer; c) treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; and/or g)decreasing the incidence of, halting or causing a regression of prostatecancer.

SUMMARY OF THE INVENTION

[0016] In one embodiment, this invention provides a class of androgenreceptor targeting agents (ARTA). The agents define a new subclass ofcompounds, which are selective androgen receptor modulators (SARM).Several of the SARM compounds have been found to have an unexpectedandrogenic and anabolic activity of a nonsteroidal ligand for theandrogen receptor. Other SARM compounds have been found to have anunexpected antiandrogenic activity of a nonsteroidal ligand for theandrogen receptor. The SARM compounds, either alone or as a composition,are useful for a) male contraception; b) treatment of a variety ofhormone-related conditions, for example conditions associated withAndrogen Decline in Aging Male (ADAM), such as fatigue, depression,decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia,osteopenia, osteoporosis, benign prostate hyperplasia, alterations inmood and cognition and prostate cancer; c) treatment of conditionsassociated with Androgen Decline in Female (ADIF), such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; and/or g)decreasing the incidence of, halting or causing a regression of prostatecancer.

[0017] In one embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound having in-vivo androgenicand anabolic activity of a nonsteroidal ligand for the androgenreceptor, said compound represented by the structure of formula I:

[0018] wherein

[0019] X is O, CH₂, NH, Se, PR, NO or NR;

[0020] T is OH, OR, —NHCOCH₃, or NHCOR;

[0021] Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

[0022] Y is CF₃, F, I, Br, Cl, CN, CR₃ or SnR₃;

[0023] Q is F, Cl, Br or I;

[0024] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH; and

[0025] R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃.

[0026] In another embodiment, the present invention provides an analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide of the compound of formula I,or any combination thereof.

[0027] In one embodiment, X in compound I is O. In another embodiment, Zin compound I is NO₂. In another embodiment, Z in compound I is CN. Inanother embodiment, Y in compound I is CF₃. In another embodiment, Q incompound I is F. In another embodiment, T in compound I is OH. Inanother embodiment, R₁ in compound I is CH₃. In another embodiment, X incompound I is O, Z is NO₂, Y is CF₃, Q is F, T is OH, and R₁ is CH₃. Inanother embodiment, X in compound I is O, Z is CN, Y is CF₃, Q is F, Tis OH, and R₁ is CH₃. In another embodiment, Q in compound I is in thepara position. In another embodiment, Z in compound I is in the paraposition. In another embodiment, Y in compound I is in the metaposition.

[0028] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound having in-vivo androgenicand anabolic activity of a nonsteroidal ligand for the androgenreceptor, said compound represented by the structure of formula II:

[0029] wherein X, Y, Z and Q are as defined above for compound I.

[0030] In another embodiment, the present invention provides an analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide of the compound of formulaII, or any combination thereof.

[0031] In one embodiment, X in compound II is O. In another embodiment,Z in compound II is NO₂. In another embodiment, Z in compound II is CN.In another embodiment, Y in compound II is CF₃. In another embodiment, Qin compound II is F. In another embodiment, X in compound II is O, Z isNO₂, Y is CF₃, and Q is F. In another embodiment, X in compound II is O,Z is CN, Y is CF₃, and Q is F.

[0032] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound having in-vivo androgenicand anabolic activity of a nonsteroidal ligand for the androgenreceptor, said compound represented by the structure of formula III:

[0033] In another embodiment, the present invention provides an analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide of the compound of formulaIII, or any combination thereof.

[0034] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound having in-vivo androgenicand anabolic activity of a nonsteroidal ligand for the androgenreceptor, said compound represented by the structure of formula IV:

[0035] In another embodiment, the present invention provides an analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide of the compound of formulaIV, or any combination thereof.

[0036] In one embodiment, the present invention provides a compositioncomprising the selective androgen receptor modulator compound of any offormulas I-IV and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof.

[0037] In another embodiment, the present invention provides apharmaceutical composition comprising the selective androgen receptormodulator compound of any of formulas I-IV and/or its analog,derivative, isomer, metabolite, pharmaceutical product, hydrate orN-oxide or any combination thereof; and a suitable carrier or diluent.

[0038] In another embodiment, the present invention provides a method ofbinding a selective androgen receptor modulator compound to an androgenreceptor, comprising the step of contacting the androgen receptor withthe selective androgen receptor modulator compound of any of formulasI-IV and/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to bind the selectiveandrogen receptor modulator compound to the androgen receptor.

[0039] In another embodiment, the present invention provides a method ofsuppressing spermatogenesis in a subject comprising contacting anandrogen receptor of the subject with the selective androgen receptormodulator compound of any of formulas I-IV and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to suppress sperm production.

[0040] In another embodiment, the present invention provides a method ofcontraception in a male subject, comprising the step of administering tothe subject the selective androgen receptor modulator compound of any offormulas I-IV and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to suppresssperm production in the subject, thereby effecting contraception in thesubject.

[0041] In another embodiment, the present invention provides a method ofhormone therapy comprising the step of contacting an androgen receptorof a subject with the selective androgen receptor modulator compound ofany of formulas I-IV and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to effect achange in an androgen-dependent condition.

[0042] In another embodiment, the present invention provides a method ofhormone replacement therapy comprising the step of contacting anandrogen receptor of a subject with the selective androgen receptormodulator compound of any of formulas I-IV and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to effect a change in an androgen-dependentcondition.

[0043] In another embodiment, the present invention provides a method oftreating a subject having a hormone related condition, comprising thestep of administering to the subject the selective androgen receptormodulator compound of any of formulas I-IV and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to effect a change in an androgen-dependentcondition.

[0044] In another embodiment, the present invention provides a method oftreating a subject suffering from prostate cancer, comprising the stepof administering to said subject the selective androgen receptormodulator compound of formulas I-IV and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate or N-oxide or any combination thereof, in an amounteffective to treat prostate cancer in the subject.

[0045] In another embodiment, the present invention provides a method ofpreventing prostate cancer in a subject, comprising the step ofadministering to the subject the selective androgen receptor modulatorcompound of formulas I-IV and/or its analog, derivative, isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate or N-oxide or any combination thereof, in an amount effective toprevent prostate cancer in the subject.

[0046] In another embodiment, the present invention provides a method ofdelaying the progression of prostate cancer in a subject suffering fromprostate cancer, comprising the step of administering to said subjectthe selective androgen receptor modulator compound of formulas I-IVand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to delay the progression ofprostate cancer in the subject.

[0047] In another embodiment, the present invention provides a method ofpreventing the recurrence of prostate cancer in a subject suffering fromprostate cancer, comprising the step of administering to said subjectthe selective androgen receptor modulator compound of formulas I-IVand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to prevent the recurrence ofprostate cancer in the subject.

[0048] In another embodiment, the present invention provides a method oftreating the recurrence of prostate cancer in a subject suffering fromprostate cancer, comprising the step of administering to said subjectthe selective androgen receptor modulator compound of formulas I-IVand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to treat the recurrence ofprostate cancer in the subject.

[0049] In another embodiment, the present invention provides a method oftreating a dry eye condition in a subject suffering from dry eyes,comprising the step of administering to said subject the selectiveandrogen receptor modulator compound of formulas I-IV and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to treat dry eyes in the subject.

[0050] In another embodiment, the present invention provides a method ofpreventing a dry eye condition in a subject, comprising the step ofadministering to said subject the selective androgen receptor modulatorcompound of formulas I-IV and/or its analog, derivative, isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate or N-oxide or any combination thereof, in an amount effective toprevent dry eyes in the subject.

[0051] The novel selective androgen receptor modulator compounds of thepresent invention, either alone or as a pharmaceutical composition, areuseful for a) male contraception; b) treatment of a variety ofhormone-related conditions, for example conditions associated with ADAM,such as fatigue, depression, decreased libido, sexual dysfunction,erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity,sarcopenia, osteopenia, benign prostate hyperplasia, and alterations inmood and cognition; c) treatment of conditions associated with ADIF,such as sexual dysfunction, decreased sexual libido, hypogonadism,sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood,depression, anemia, hair loss, obesity, endometriosis, breast cancer,uterine cancer and ovarian cancer; d) treatment and/or prevention ofacute and/or chronic muscular wasting conditions; e) preventing and/ortreating dry eye conditions; f) oral androgen replacement therapy;and/or g) decreasing the incidence of, halting or causing a regressionof prostate cancer.

[0052] The selective androgen receptor modulator compounds of thepresent invention offer a significant advance over steroidal androgentreatment because the selective androgen receptor modulator compounds ofthe present invention have been shown in-vivo to have an androgenic andanabolic activity of a nonsteroidal ligand for the androgen receptor.Thus, the selective androgen receptor modulator compounds have anandrogenic and anabolic activity of a nonsteroidal ligand for theandrogen receptor and will not be accompanied by serious side effects,inconvenient modes of administration, or high costs and still have theadvantages of oral bioavailability, lack of cross-reactivity with othersteroid receptors, and long biological half-lives.

BRIEF DESCRIPTION OF THE FIGURES.

[0053] The present invention will be understood and appreciated morefully from the following detailed description taken in conjunction withthe appended figures which depict:

[0054]FIG. 1: Androgenic and Anabolic activity of Compound V in rats.Rats were left untreated (intact control), castrated (castratedcontrol), treated with testosterone propionate (TP), or treated withCompound V, and the body weight gain as well as the weight ofandrogen-responsive tissues (prostate, semimal vesicles and levator animuscle) was determined.

[0055]FIG. 2: Androgenic and Anabolic activity of Compound V in rats.Rats were left untreated (intact control), castrated (castratedcontrol), treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mg/day testosteronepropionate (TP), or treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mg/dayCompound V, and the weight of androgen-responsive tissues (prostate,semimal vesicles and levator ani muscle) was determined.

[0056]FIG. 3: Androgenic and Anabolic activity of Compound III in rats.Rats were left untreated (intact control), castrated (castratedcontrol), treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mg/day testosteronepropionate (TP), or treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mg/dayCompound III, and the weight of androgen-responsive tissues (prostate,semimal vesicles and levator ani muscle) was determined.

[0057]FIG. 4: Average plasma concentration-time profiles of Compound Vin beagle dogs after IV administration at 3 and 10 mg/kg.

[0058]FIG. 5: Average plasma concentration-time profiles of Compound Vin beagle dogs after PO administration as solution at 10 mg/kg.

[0059]FIG. 6: Average plasma concentration-time profiles of Compound Vin beagle dogs after IV administration as capsules at mg/kg.

[0060]FIG. 7: Effects of Compound III and Compound V on LH Levels.

[0061]FIG. 8: Effects of Compound III and Compound V on FSH Levels.

[0062]FIG. 9: Synthesis scheme of Compound V.

DETAILED DESCRIPTION OF THE INVENTION

[0063] In one embodiment, This invention provides a class of androgenreceptor targeting agents (ARTA). The agents define a new subclass ofcompounds, which are selective androgen receptor modulators (SARM).Several of the SARM compounds have been found to have an unexpectedandrogenic and anabolic activity of a nonsteroidal ligand for theandrogen receptor. Other SARM compounds have been found to have anunexpected antiandrogenic activity of a nonsteroidal ligand for theandrogen receptor. The SARM compounds, either alone or as a composition,are useful for a) male contraception; b) treatment of a variety ofhormone-related conditions, for example conditions associated withAndrogen Decline in Aging Male (ADAM), such as fatigue, depression,decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia,osteopenia, osteoporosis, benign prostate hyperplasia, alterations inmood and cognition and prostate cancer; c) treatment of conditionsassociated with Androgen Decline in Female (ADIF), such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; and/or g)decreasing the incidence of, halting or causing a regression of prostatecancer.

[0064] In one embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula I:

[0065] wherein

[0066] X is O, CH₂, NH, Se, PR, NO or NR;

[0067] T is OH, OR, —NHCOCH₃, or NHCOR;

[0068] Z is NO₂, CN, COOH, COR, NHCOR or CONHR;

[0069] Y is CF₃, F, I, Br, Cl, CN, CR₃ or SnR₃;

[0070] Q is F, Cl, Br or I;

[0071] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH; and

[0072] R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃.

[0073] In one embodiment, this invention provides an analog of thecompound of formula I. In another embodiment, this invention provides aderivative of the compound of formula I. In another embodiment, thisinvention provides an isomer of the compound of formula I. In anotherembodiment, this invention provides a metabolite of the compound offormula I. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula I. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula I. In another embodiment, this inventionprovides a hydrate of the compound of formula I. In another embodiment,this invention provides an N-oxide of the compound of formula I. Inanother embodiment, this invention provides a combination of any of ananalog, derivative, metabolite, isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate or N-oxide of the compound offormula I.

[0074] In one embodiment, the present invention provides a compound offormula I wherein X is O. In another embodiment, the present inventionprovides a compound of formula I wherein Z is NO₂. In anotherembodiment, the present invention provides a compound of formula Iwherein Z is CN. In another embodiment, the present invention provides acompound of formula I wherein Y is CF₃. In another embodiment, thepresent invention provides a compound of formula I wherein Q is F. Inanother embodiment, the present invention provides a compound of formulaI wherein T is OH. In another embodiment, the present invention providesa compound of formula I wherein R₁ is CH₃. In another embodiment, thepresent invention provides a compound of formula I wherein X is O, Z isNO₂, Y is CF₃, Q is F, T is OH, and R₁ is CH₃. In another embodiment,the present invention provides a compound of formula I wherein X is O, Zis CN, Y is CF₃, Q is F, T is OH, and R₁ is CH₃.

[0075] The substituents Z and Y can be in any position of the ringcarrying these substituents (hereinafter “A ring”). In one embodiment,the substituent Z is in the para position of the A ring. In anotherembodiment, the substituent Y is in the meta position of the A ring. Inanother embodiment, the substituent Z is in the para position of the Aring and substituent Y is in the meta position of the A ring. . Inanother embodiment, the substitutent Z is NO₂ and is in the paraposition of the A ring. In another embodiment, the substitutent Z is CNand is in the para position of the A ring. In another embodiment, thesubstitutent Y is CF₃ and is in the meta position of the A ring.

[0076] The substituent Q can be in any position of the ring carryingthese substituents (hereinafter “B ring”). In one embodiment, thesubstitutent Q is in the para position of the B ring. In anotherembodiment, the substitutent Q is in the para position of the B ring. Inanother embodiment, the substitutent Q is F and is in the para positionof the B ring.

[0077] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula II:

[0078] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound having in-vivo androgenicand anabolic activity of a nonsteroidal ligand for the androgenreceptor, said compound represented by the structure of formula II:

[0079] wherein X, Y, Z and Q are as defined above for compound I.

[0080] In one embodiment, this invention provides an analog of thecompound of formula II. In another embodiment, this invention provides aderivative of the compound of formula II. In another embodiment, thisinvention provides an isomer of the compound of formula II. In anotherembodiment, this invention provides a metabolite of the compound offormula II. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula II. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula II. In another embodiment, this inventionprovides a hydrate of the compound of formula II. In another embodiment,this invention provides an N-oxide of the compound of formula II. Inanother embodiment, this invention provides a combination of any of ananalog, derivative, metabolite, isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate or N-oxide of the compound offormula II.

[0081] In one embodiment, the present invention provides a compound offormula II wherein X is O. In another embodiment, the present inventionprovides a compound of formula II wherein Z is NO₂. In anotherembodiment, the present invention provides a compound of formula IIwherein Z is CN. In another embodiment, the present invention provides acompound of formula II wherein is CF₃. In another embodiment, thepresent invention provides a compound of formula II wherein Q is F. Inanother embodiment, the present invention provides a compound of formulaII wherein X is O, Z is NO₂, Y is CF₃, and Q is F. In anotherembodiment, the present invention provides a compound of formula IIwherein X is O, Z is CN, Y is CF₃, and Q is F.

[0082] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound having in-vivo androgenicand anabolic activity of a nonsteroidal ligand for the androgenreceptor, said compound represented by the structure of formula III:

[0083] In one embodiment, this invention provides an analog of thecompound of formula III. In another embodiment, this invention providesa derivative of the compound of formula III. In another embodiment, thisinvention provides an isomer of the compound of formula III. In anotherembodiment, this invention provides a metabolite of the compound offormula III. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula III. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula III. In another embodiment, this inventionprovides a hydrate of the compound of formula III. In anotherembodiment, this invention provides an N-oxide of the compound offormula III. In another embodiment, this invention provides acombination of any of an analog, derivative, metabolite, isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide of the compound of formula III.

[0084] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound having in-vivo androgenicand anabolic activity of a nonsteroidal ligand for the androgenreceptor, said compound represented by the structure of formula IV:

[0085] In one embodiment, this invention provides an analog of thecompound of formula IV. In another embodiment, this invention provides aderivative of the compound of formula IV. In another embodiment, thisinvention provides an isomer of the compound of formula IV. In anotherembodiment, this invention provides a metabolite of the compound offormula IV. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula IV. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula IV. In another embodiment, this inventionprovides a hydrate of the compound of formula IV. In another embodiment,this invention provides an N-oxide of the compound of formula IV. Inanother embodiment, this invention provides a combination of any of ananalog, derivative, metabolite, isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate or N-oxide of the compound offormula IV.

[0086] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula V:

[0087] In one embodiment, this invention provides an analog of thecompound of formula V. In another embodiment, this invention provides aderivative of the compound of formula V. In another embodiment, thisinvention provides an isomer of the compound of formula V. In anotherembodiment, this invention provides a metabolite of the compound offormula V. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula V. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula V. In another embodiment, this inventionprovides a hydrate of the compound of formula V. In another embodiment,this invention provides an N-oxide of the compound of formula V. Inanother embodiment, this invention provides a combination of any of ananalog, derivative, metabolite, isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate or N-oxide of the compound offormula V.

[0088] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula VI:

[0089] In one embodiment, this invention provides an analog of thecompound of formula VI. In another embodiment, this invention provides aderivative of the compound of formula VI. In another embodiment, thisinvention provides an isomer of the compound of formula VI. In anotherembodiment, this invention provides a metabolite of the compound offormula VI. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VI. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VI. In another embodiment, this inventionprovides a hydrate of the compound of formula VI. In another embodiment,this invention provides an N-oxide of the compound of formula VI. Inanother embodiment, this invention provides a combination of any of ananalog, derivative, metabolite, isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate or N-oxide of the compound offormula VI.

[0090] In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula VII:

[0091] In one embodiment, this invention provides an analog of thecompound of formula VII. In another embodiment, this invention providesa derivative of the compound of formula VII. In another embodiment, thisinvention provides an isomer of the compound of formula VII. In anotherembodiment, this invention provides a metabolite of the compound offormula VII. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VII. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VII. In another embodiment, this inventionprovides a hydrate of the compound of formula VII. In anotherembodiment, this invention provides an N-oxide of the compound offormula VII. In another embodiment, this invention provides acombination of any of an analog, derivative, metabolite, isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide of the compound of formula VII.

[0092] The substituent R is defined herein as an alkyl, haloalkyl,dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃, CF₂CF₃; aryl, phenyl,halogen, alkenyl, or hydroxyl (OH).

[0093] An “alkyl” group refers to a saturated aliphatic hydrocarbon,including straight-chain, branched-chain and cyclic alkyl groups. In oneembodiment, the alkyl group has 1-12 carbons. In another embodiment, thealkyl group has 1-7 carbons. In another embodiment, the alkyl group has1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. Thealkyl group may be unsubstituted or substituted by one or more groupsselected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio andthioalkyl.

[0094] A “haloalkyl” group refers to an alkyl group as defined above,which is substituted by one or more halogen atoms, e.g. by F, Cl, Br orI.

[0095] An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido,dialklylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thioor thioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.

[0096] A “hydroxyl” group refers to an OH group. An “alkenyl” grouprefers to a group having at least one carbon to carbon double bond. Ahalo group refers to F, Cl, Br or I.

[0097] An “arylalkyl” group refers to an alkyl bound to an aryl, whereinalkyl and aryl are as defined above. An example of an aralkyl group is abenzyl group.

[0098] As contemplated herein, the present invention relates to the useof a SARM compound and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or combinations thereof. In one embodiment, the inventionrelates to the use of an analog of the SARM compound. In anotherembodiment, the invention relates to the use of a derivative of the SARMcompound. In another embodiment, the invention relates to the use of anisomer of the SARM compound. In another embodiment, the inventionrelates to the use of a metabolite of the SARM compound. In anotherembodiment, the invention relates to the use of a pharmaceuticallyacceptable salt of the SARM compound. In another embodiment, theinvention relates to the use of a pharmaceutical product of the SARMcompound. In another embodiment, the invention relates to the use of ahydrate of the SARM compound. In another embodiment, the inventionrelates to the use of an N-oxide of the SARM compound.

[0099] As defined herein, the term “isomer” includes, but is not limitedto, optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

[0100] In one embodiment, this invention encompasses the use of variousoptical isomers of the SARM compound. It will be appreciated by thoseskilled in the art that the SARMs of the present invention contain atleast one chiral center. Accordingly, the SARMs used in the methods ofthe present invention may exist in, and be isolated in, optically-activeor racemic forms. Some compounds may also exhibit polymorphism. It is tobe understood that the present invention encompasses any racemic,optically-active, polymorphic, or stereroisomeric form, or mixturesthereof, which form possesses properties useful in the treatment ofandrogen-related conditions described herein. In one embodiment, theSARMs are the pure (R)-isomers. In another embodiment, the SARMs are thepure (S)-isomers. In another embodiment, the SARMs are a mixture of the(R) and the (S) isomers. In another embodiment, the SARMs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

[0101] The invention includes pharmaceutically acceptable salts ofamino-substituted compounds with organic and inorganic acids, forexample, citric acid and hydrochloric acid. The invention also includesN-oxides of the amino substituents of the compounds described herein.Pharmaceutically acceptable salts can also be prepared from the phenoliccompounds by treatment with inorganic bases, for example, sodiumhydroxide. Also, esters of the phenolic compounds can be made withaliphatic and aromatic carboxylic acids, for example, acetic acid andbenzoic acid esters.

[0102] This invention further includes derivatives of the SARMcompounds. The term “derivatives” includes but is not limited to etherderivatives, acid derivatives, amide derivatives, ester derivatives andthe like. In addition, this invention further includes hydrates of theSARM compounds. The term “hydrate” includes but is not limited tohemihydrate, monohydrate, dihydrate, trihydrate and the like.

[0103] This invention further includes metabolites of the SARMcompounds. The term “metabolite” means any substance produced fromanother substance by metabolism or a metabolic process.

[0104] This invention further includes pharmaceutical products of theSARM compounds. The term “pharmaceutical product” means a compositionsuitable for pharmaceutical use (pharmaceutical composition), as definedherein.

[0105] Biological Activity of Selective Androgen Modulator Compounds

[0106] The compounds provided herein are a new subclass of compoundswhich are selective androgen receptor modulators (SARM which are usefulfor oral testosterone replacement therapy which have an unexpectedin-vivo activity for an androgenic and anabolic activity of anonsteroidal ligand for the androgen receptor. Further, appropriatelysubstituted compounds are effective to treat prostate cancer and areuseful for imaging of prostate cancer. The SARM compounds demonstrate anin-vivo androgenic and anabolic activity of a nonsteroidal ligand forthe androgen receptor.

[0107] As contemplated herein, the appropriately substituted SARMcompounds of the present invention are useful for a) male contraception;b) treatment of a variety of hormone-related conditions, for exampleconditions associated with Androgen Decline in Aging Male (ADAM), suchas fatigue, depression, decreased libido, sexual dysfunction, erectiledysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity,sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia,alterations in mood and cognition and prostate cancer; c) treatment ofconditions associated with ADIF, such as sexual dysfunction, decreasedsexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis,alterations in cognition and mood, depression, anemia, hair loss,obesity, endometriosis, breast cancer, uterine cancer and ovariancancer; d) treatment and/or prevention of acute and/or chronic muscularwasting conditions; e) preventing and/or treating dry eye conditions; f)oral androgen replacement therapy; and/or g) decreasing the incidenceof, halting or causing a regression of prostate cancer.

[0108] As used herein, receptors for extracellular signaling moleculesare collectively referred to as “cell signaling receptors”. Many cellsignaling receptors are transmembrane proteins on a cell surface; whenthey bind an extracellular signaling molecule (i.e., a ligand), theybecome activated so as to generate a cascade of intracellular signalsthat alter the behavior of the cell. In contrast, in some cases, thereceptors are inside the cell and the signaling ligand has to enter thecell to activate them; these signaling molecules therefore must besufficiently small and hydrophobic to diffuse across the plasma membraneof the cell.

[0109] Steroid hormones are one example of small hydrophobic moleculesthat diffuse directly across the plasma membrane of target cells andbind to intracellular cell signaling receptors. These receptors arestructurally related and constitute the intracellular receptorsuperfamily (or steroid-hormone receptor superfamily). Steroid hormonereceptors include progesterone receptors, estrogen receptors, androgenreceptors, glueocorticoid receptors, and mineralocorticoid receptors.The present invention is particularly directed to androgen receptors.

[0110] In addition to ligand binding to the receptors, the receptors canbe blocked to prevent ligand binding. When a substance binds to areceptor, the three-dimensional structure of the substance fits into aspace created by the three-dimensional structure of the receptor in aball and socket configuration. The better the ball fits into the socket,the more tightly it is held. This phenomenon is called affinity. If theaffinity of a substance is greater than the original hormone, it willcompete with the hormone and bind the binding site more frequently. Oncebound, signals may be sent through the receptor into the cells, causingthe cell to respond in some fashion. This is called activation. Onactivation, the activated receptor then directly regulates thetranscription of specific genes. But the substance and the receptor mayhave certain attributes, other than affinity, in order to activate thecell. Chemical bonds between atoms of the substance and the atoms of thereceptors may form. In some cases, this leads to a change in theconfiguration of the receptor, which is enough to begin the activationprocess (called signal transduction).

[0111] In one embodiment, the present invention is directed to selectiveandrogen receptor modulator compounds which are agonist compounds. Areceptor agonist is a substance which binds receptors and activatesthem. Thus, in one embodiment, the SARM compounds of the presentinvention are useful in binding to and activating steroidal hormonereceptors. In one embodiment, the agonist compound of the presentinvention is an agonist which binds the androgen receptor. In anotherembodiment, the compound has high affinity for the androgen receptor. Inanother embodiment, the agonist compound also has anabolic activity. Inanother embodiment, the present invention provides selective androgenmodulator compounds which have agonistic and anabolic activity of anonsteroidal compound for the androgen receptor.

[0112] In another embodiment, other selective androgen receptormodulator compounds are antagonist compounds. A receptor antagonist is asubstance which binds receptors and inactivates them. Thus, in oneembodiment, the SARM compounds of the present invention are useful inbinding to and inactivating steroidal hormone receptors. In oneembodiment, the antagonist compound of the present invention is anantagonist which binds the androgen receptor. In another embodiment, thecompound has high affinity for the androgen receptor.

[0113] In yet another embodiment, the SARM compounds of the presentinvention can be classified as partial AR agonist/antagonists. The SARMsare AR agonists in some tissues, to cause increased transcription ofAR-responsive genes (e.g. muscle anabolic effect). In other tissues,these compounds serve as inhibitors at the AR to prevent agonisticeffects of the native androgens.

[0114] Assays to determine whether the compounds of the presentinvention are AR agonists or antagonists are well known to a personskilled in the art. For example, AR agonistic activity can be determinedby monitoring the ability of the SARM compounds to maintain and/orstimulate the growth of AR containing tissue such as prostate andseminal vesicles, as measured by weight. AR antagonistic activity can bedetermined by monitoring the ability of the SARM compounds to inhibitthe growth of AR containing tissue.

[0115] The compounds of the present invention bind either reversibly orirreversibly to an androgen receptor. In one embodiment, the androgenreceptor is an androgen receptor of a mammal. In another embodiment, theandrogen receptor is an androgen receptor of a human. In one embodiment,the SARM compounds bind reversibly to the androgen receptor of a mammal,for example a human. Reversible binding of a compound to a receptormeans that a compound can detach from the receptor after binding.

[0116] In another embodiment, the SARM compounds bind irreversibly tothe androgen receptor of a mammal, for example a human. Thus, in oneembodiment, the compounds of the present invention may contain afunctional group (e.g. affinity label) that allows alkylation of theandrogen receptor (i.e. covalent bond formation). Thus, in this case,the compounds are alkylating agents which bind irreversibly to thereceptor and, accordingly, cannot be displaced by a steroid, such as theendogenous ligands DHT and testosterone. An “alkylating agent” isdefined herein as an agent which alkylates (forms a covalent bond) witha cellular component, such as DNA, RNA or enzyme. It is a highlyreactive chemical that introduces alkyl radicals into biologicallyactive molecules and thereby prevents their proper functioning. Thealkylating moiety is an electrophilic group that interacts withnucleophilic moieties in cellular components.

[0117] According to one embodiment of the present invention, a method isprovided for binding the SARM compounds of the present invention to anandrogen receptor by contacting the receptor with a SARM compound and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate or N-oxide or any combinationthereof, under conditions effective to cause the selective androgenreceptor modulator compound to bind the androgen receptor. The bindingof the selective androgen receptor modulator compounds to the androgenreceptor enables the compounds of the present invention to be useful asa male contraceptive and in a number of hormone therapies. The agonistcompounds bind to and activate the androgen receptor. The antagonistcompounds bind to and inactivate the androgen receptor. Binding of theagonist or antagonist compounds is either reversible or irreversible.

[0118] According to one embodiment of the present invention, a method isprovided for suppressing spermatogenesis in a subject by contacting anandrogen receptor of the subject with a SARM compound of the presentinvention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to bind theselective androgen receptor modulator compound to the androgen receptorand suppress spermatogenesis.

[0119] According to another embodiment of the present invention, amethod is provided for contraception in a male subject, comprising thestep of administering to the subject a SARM compound of the presentinvention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to suppresssperm production in the subject, thereby effecting contraception in thesubject.

[0120] According to another embodiment of the present invention, amethod is provided for hormonal therapy in a patient (i.e., onesuffering from an androgen-dependent condition) which includescontacting an androgen receptor of a patient with a SARM compound of thepresent invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to bind theselective androgen receptor modulator compound to the androgen receptorand effect a change in an androgen-dependent condition.

[0121] According to another embodiment of the present invention, amethod is provided for hormone replacement therapy in a patient (i.e.,one suffering from an androgen-dependent condition) which includescontacting an androgen receptor of a patient with a SARM compound of thepresent invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to bind theselective androgen receptor modulator compound to the androgen receptorand effect a change in an androgen-dependent condition.

[0122] According to another embodiment of the present invention, amethod is provided for treating a subject having a hormone relatedcondition, which includes administering to the subject a SARM compoundof the present invention and/or its analog, derivative, isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate or N-oxide or any combination thereof, in an amount effective tobind the SARM compound to the androgen receptor and effect a change inan androgen-dependent condition.

[0123] Androgen-dependent conditions which may be treated according tothe present invention include those conditions which are associated withaging, such as hypogonadism, sarcopenia, erythropoiesis, osteoporosis,and any other conditions later determined to be dependent upon lowandrogen (e.g., testosterone) levels.

[0124] According to another embodiment of the present invention, amethod is provided for treating a subject suffering from prostatecancer, comprising the step of administering to the subject a SARMcompound of the present invention and/or its analog, derivative, isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate or N-oxide or any combination thereof, in an amount effective totreat prostate cancer in the subject.

[0125] According to another embodiment of the present invention, amethod is provided for preventing prostate cancer in a subject,comprising the step of administering to the subject a SARM compound ofthe present invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to treatprevent prostate cancer in the subject.

[0126] According to another embodiment of the present invention, amethod is provided for delaying the progression of prostate cancer in asubject suffering from prostate cancer, comprising the step ofadministering to the subject a SARM compound of the present inventionand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to delay the progression ofprostate cancer in the subject.

[0127] According to another embodiment of the present invention, amethod is provided for preventing the recurrence of prostate cancer in asubject suffering from prostate cancer, comprising the step ofadministering to the subject a SARM compound of the present inventionand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to prevent the recurrence ofprostate cancer in the subject.

[0128] According to another embodiment of the present invention, amethod is provided for treating the recurrence of prostate cancer in asubject suffering from prostate cancer, comprising the step ofadministering to the subject a SARM compound of the present inventionand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to treat the recurrence ofprostate cancer in the subject.

[0129] Furthermore, stimulation of the Androgen Receptor stimulates theproduction of tears, and thus the SARM compounds of the presentinvention may be used to treat dry eye conditions. Therefore, accordingto another embodiment of the present invention, a method is provided fortreating a dry eye condition in a subject suffering from dry eyes,comprising the step of administering to said subject the selectiveandrogen receptor modulator compound of formulas I-IV and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to treat dry eyes in the subject.

[0130] According to another embodiment of the present invention, amethod is provided for preventing a dry eye condition in a subject,comprising the step of administering to said subject the selectiveandrogen receptor modulator compound of formulas I-IV and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to prevent dry eyes in the subject.

[0131] As defined herein, “contacting” means that the SARM compound ofthe present invention is introduced into a sample containing the enzymein a test tube, flask, tissue culture, chip, array, plate, microplate,capillary, or the like, and incubated at a temperature and timesufficient to permit binding of the SARM to the enzyme. Methods forcontacting the samples with the SARM or other specific bindingcomponents are known to those skilled in the art and may be selecteddepending on the type of assay protocol to be run. Incubation methodsare also standard and are known to those skilled in the art.

[0132] In another embodiment, the term “contacting” means that the SARMcompound of the present invention is introduced into a subject receivingtreatment, and the SARM compound is allowed to come in contact with theandrogen receptor in vivo.

[0133] As used herein, the term “teating” includes preventative as wellas disorder remitative treatment. As used herein, the terms “reducing”,“suppressing” and “inhibiting” have their commonly understood meaning oflessening or decreasing. As used herein, the term “progression” meansincreasing in scope or severity, advancing, growing or becoming worse.As used herein, the term “recurrence” means the return of a diseaseafter a remission.

[0134] As used herein, the term “administering” refers to bringing asubject in contact with a SARM compound of the present invention. Asused herein, administration can be accomplished in vitro, i.e. in a testtube, or in vivo, i.e. in cells or tissues of living organisms, forexample humans. In one embodiment, the present invention encompassesadministering the compounds of the present invention to a subject.

[0135] The term “libido, as used herein, means sexual desire.

[0136] The term “erectile”, as used herein, means capable of beingerected. An erectile tissue is a tissue, which is capable of beinggreatly dilated and made rigid by the distension of the numerous bloodvessels which it contains.

[0137] “Hypogonadism” is a condition resulting from or characterised byabnormally decreased functional activity of the gonads, with retardationof growth and sexual development. “Osteopenia” refers to decreasedcalcification or density of bone. This is a term which encompasses allskeletal systems in which such a condition is noted.

[0138] “Osteoporosis” refers to a thinning of the bones with reductionin bone mass due to depletion of calcium and bone protein. Osteoporosispredisposes a person to fractures, which are often slow to heal and healpoorly. Unchecked osteoporosis can lead to changes in posture, physicalabnormality, and decreased mobility.

[0139] “BPH (benign prostate hyperplasia)” is a nonmalignant enlargementof the prostate gland, and is the most common non-malignantproliferative abnormality found in any internal organ and the majorcause of morbidity in the adult male. BPH occurs in over 75% of men over50 years of age, reaching 88% prevalence by the ninth decade. BPHfrequently results in a gradual squeezing of the portion of the urethrawhich traverses the prostate (prostatic urethra). This causes patientsto experience a frequent urge to urinate because of incomplete emptyingof the bladder and urgency of urination. The obstruction of urinary flowcan also lead to a general lack of control over urination, includingdifficulty initiating urination when desired, as well as difficulty inpreventing urinary flow because of the inability to empty urine from thebladder, a condition known as overflow urinary incontinence, which canlead to urinary obstruction and to urinary failure.

[0140] “Cognition” refers to the process of knowing, specifically theprocess of being aware, knowing, thinking, learning and judging.Cognition is related to the fields of psychology, linguistics, computerscience, neuroscience, mathematics, ethology and philosophy. The term“mood” refers to a temper or state of the mind. As contemplated herein,alterations means any change for the positive or negative, in cognitionand/or mood.

[0141] The term “depression” refers to an illness that involves thebody, mood and thoughts, that affects the way a person eats, sleeps andthe way one feels about oneself, and thinks about things. The signs andsymptoms of depression include loss of interest in activities, loss ofappetite or overeating, loss of emotional expression, an empty mood,feelings of hopelessness, pessimism, guilt or helplessness, socialwithdrawal, fatigue, sleep disturbances, trouble concentrating,remembering, or making decisions, restlessness, irritability, headaches,digestive disorders or chronic pain.

[0142] The term “hair loss”, medically known as alopecia, refers tobaldness as in the very common type of male-pattern baldness. Baldnesstypically begins with patch hair loss on the scalp and sometimesprogresses to complete baldness and even loss of body hair. Hair lossaffects both males and females.

[0143] “Anemia” refers to the condition of having less than the normalnumber of red blood cells or less than the normal quantity of hemoglobinin the blood. The oxygen-carrying capacity of the blood is, therefore,decreased. Persons with anemia may feel tired and fatigue easily, appearpale, develop palpitations and become usually short of breath. Anemia iscaused by four basic factors: a) hemorrhage (bleeding); b) hemolysis(excessive destruction of red blood cells); c) underproduction of redblood cells; and d) not enough normal hemoglobin. There are many formsof anemia, including aplastic anemia, benzene poisoning, Fanconi anemia,hemolytic disease of the newborn, hereditary spherocytosis, irondeficiency anemia, osteopetrosis, pernicious anemia, sickle celldisease, thalassemia, myelodysplastic syndrome, and a variety of bonemarrow diseases. As contemplated herein, the SARM compounds of thepresent invention are useful in preventing and/or treating any one ormore of the above-listed forms of anemia.

[0144] “Obesity” refers to the state of being well above one's normalweight. Traditionally, a person is considered to be obese if they aremore than 20 percent over their ideal weight. Obesity has been moreprecisely defined by the National Institute of Health (NIH) as a Body toMass Index (BMI) of 30 or above. Obesity is often multifactorial, basedon both genetic and behavioral factors. Overweight due to obesity is asignificant contributor to health problems. It increases the risk ofdeveloping a number of diseases including: Type 2 (adult-onset)diabetes; high blood pressure (hypertension); stroke (cerebrovascularaccident or CVA); heart attack (myocardial infarction or MI); heartfailure (congestive heart failure); cancer (certain forms such as cancerof the prostate and cancer of the colon and rectum); gallstones andgallbladder disease (cholecystitis); Gout and gouty arthritis;osteoarthritis (degenerative arthritis) of the knees, hips, and thelower back; sleep apnea (failure to breath normally during sleep,lowering blood oxygen); and Pickwickian syndrome (obesity, red face,underventilation and drowsiness). As contemplated herein, the term“obesity” includes any one of the above-listed obesity-relatedconditions and diseases. Thus the SARM compounds of the presentinvention are useful in preventing and/or treating obesity and any oneor more of the above-listed obesity-related conditions and diseases.

[0145] “Prostate cancer” is one of the most frequently occurring cancersamong men in the United States, with hundreds of thousands of new casesdiagnosed each year. Over sixty percent of newly diagnosed cases ofprostate cancer are found to be pathologically advanced, with no cureand a dismal prognosis. One third of all men over 50 years of age have alatent form of prostate cancer that may be activated into thelife-threatening clinical prostate cancer form. The frequency of latentprostatic tumors has been shown to increase substantially with eachdecade of life from the 50s (5.3-14%) to the 90s (40-80%). The number ofpeople with latent prostate cancer is the same across all cultures,ethnic groups, and races, yet the frequency of clinically aggressivecancer is markedly different. This suggests that environmental factorsmay play a role in activating latent prostate cancer.

[0146] In one embodiment, the methods of the present invention compriseadministering a SARM compound as the sole active ingredient. However,also encompassed within the scope of the present invention are methodsfor hormone therapy, for treating prostate cancer, for delaying theprogression of prostate cancer, and for preventing and/or treating therecurrence of prostate cancer, which comprise administering the SARMcompounds in combination with one or more therapeutic agents. Theseagents include, but are not limited to: LHRH analogs, reversibleantiandrogens, antiestrogens, anticancer drugs, 5-alpha reductaseinhibitors, aromatase inhibitors, progestins, agents acting throughother nuclear hormone receptors, selective estrogen receptor modulators(SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine,bisphosphonate, and one or more additional SARMS.

[0147] Thus, in one embodiment, the methods of the present inventioncomprise administering the selective androgen receptor modulatorcompound, in combination with an LHRH analog. In another embodiment, themethods of the present invention comprise administering a selectiveandrogen receptor modulator compound, in combination with a reversibleantiandrogen, In another embodiment, the methods of the presentinvention comprise administering a selective androgen receptor modulatorcompound, in combination with an antiestrogen. In another embodiment,the methods of the present invention comprise administering a selectiveandrogen receptor modulator compound, in combination with an anticancerdrug. In another embodiment, the methods of the present inventioncomprise administering a selective androgen receptor modulator compound,in combination with a 5-alpha reductase inhibitor. In anotherembodiment, the methods of the present invention comprise administeringa selective androgen receptor modulator compound, in combination with anaromatase inhibitor. In another embodiment, the methods of the presentinvention comprise administering a selective androgen receptor modulatorcompound, in combination with a progestin. In another embodiment, themethods of the present invention comprise administering a selectiveandrogen receptor modulator compound, in combination with an agentacting through other nuclear hormone receptors. In another embodiment,the methods of the present invention comprise administering a selectiveandrogen receptor modulator compound, in combination with a selectiveestrogen receptor modulators (SERM). In another embodiment, the methodsof the present invention comprise administering a selective androgenreceptor modulator compound, in combination with a progesterone. Inanother embodiment, the methods of the present invention compriseadministering a selective androgen receptor modulator compound, incombination with an estrogen. In another embodiment, the methods of thepresent invention comprise administering a selective androgen receptormodulator compound, in combination with a PDE5 inhibitor. In anotherembodiment, the methods of the present invention comprise administeringa selective androgen receptor modulator compound, in combination withapomorphine. In another embodiment, the methods of the present inventioncomprise administering a selective androgen receptor modulator compound,in combination with a bisphosphonate. In another embodiment, the methodsof the present invention comprise administering a selective androgenreceptor modulator compound, in combination with one or more additionalSARMS.

[0148] In one embodiment, the present invention provides a compositionand a pharmaceutical composition comprising the selective androgenreceptor modulator compound of any of formulas I-VI and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof;and a suitable carrier or diluent.

[0149] As used herein, “pharmaceutical composition” meanstherapeutically effective amounts of the SARM together with suitablediluents, preservatives, solubilizers, emulsifiers, adjuvant and/orcarriers. A “therapeutically effective amount” as used herein refers tothat amount which provides a therapeutic effect for a given conditionand administration regimen. Such compositions are liquids or Lyophilizedor otherwise dried formulations and include diluents of various buffercontent (e.g., Tris-HCI., acetate, phosphate), pH and ionic strength,additives such as albumin or gelatin to prevent absorption to surfaces,detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts),solubilizing agents (e.g., glycerol, polyethylene glycerol),anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives(e.g., Thimerosal, benzyl alcohol, parabens), bulking substances ortonicity modifiers (e.g., lactose, mannitol), covalent attachment ofpolymers such as polyethylene glycol to the protein, complexation withmetal ions, or incorporation of the material into or onto particulatepreparations of polymeric compounds such as polylactic acid, polglycolicacid, hydrogels, etc, or onto liposomes, microemulsions, micelles,unilamellar or multilamellar vesicles, erythrocyte ghosts, orspheroplasts.) Such compositions will influence the physical state,solubility, stability, rate of in vivo release, and rate of in vivoclearance. Controlled or sustained release compositions includeformulation in lipophilic depots (e.g., fatty acids, waxes, oils).

[0150] Also comprehended by the invention are particulate compositionscoated with polymers (e.g., poloxamers or poloxamines). Otherembodiments of the compositions of the invention incorporate particulateforms protective coatings, protease inhibitors or permeation enhancersfor various routes of administration, including parenteral, pulmonary,nasal and oral. In one embodiment the pharmaceutical composition isadministered parenterally, paracancerally, transmucosally,transdermally, intramuscularly, intravenously, intradermally,subcutaneously, intravaginally, intraperitonealy, intraventricularly,intracranially or intratumorally.

[0151] Further, as used herein “pharmaceutically acceptable carriers”are well known to those skilled in the art and include, but are notlimited to, 0.01-0.1M and preferably 0.05M phosphate buffer or 0.8%saline. Additionally, such pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, and emulsions. Examplesof non-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia.

[0152] Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose, andthe like. Preservatives and other additives may also be present, suchas, for example, antimicrobials, antioxidants, collating agents, inertgases and the like.

[0153] Controlled or sustained release compositions include formulationin lipophilic depots (e.g. fatty acids, waxes, oils). Also comprehendedby the invention are particulate compositions coated with polymers (e.g.poloxamers or poloxamines) and the compound coupled to antibodiesdirected against tissue-specific receptors, ligands or antigens orcoupled to ligands of tissue-specific receptors.

[0154] Other embodiments of the compositions of the inventionincorporate particulate forms, protective coatings, protease inhibitorsor permeation enhancers for various routes of administration, includingparenteral, pulmonary, nasal and oral.

[0155] Compounds modified by the covalent attachment of water-solublepolymers such as polyethylene glycol, copolymers of polyethylene glycoland polypropylene glycol, carboxymethyl cellulose, dextran, polyvinylalcohol, polyvinylpyrrolidone or polyproline are known to exhibitsubstantially longer half-lives in blood following intravenous injectionthan do the corresponding unmodified compounds (Abuchowski et al., 1981;Newmark et al., 1982; and Katre et al., 1987). Such modifications mayalso increase the compound's solubility in aqueous solution, eliminateaggregation, enhance the physical and chemical stability of thecompound, and greatly reduce the immunogenicity and reactivity of thecompound. As a result, the desired in vivo biological activity may beachieved by the administration of such polymer-compound abducts lessfrequently or in lower doses than with the unmodified compound.

[0156] In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit.Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980);Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment,polymeric materials can be used. In yet another embodiment, a controlledrelease system can be placed in proximity to the therapeutic target,i.e., the brain, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984). Other controlled release systems arediscussed in the review by Langer (Science 249:1527-1533 (1990).

[0157] The pharmaceutical preparation can comprise the SARM agent alone,or can further include a pharmaceutically acceptable carrier and can bein solid or liquid form such as tablets, powders, capsules, pellets,solutions, suspensions, elixirs, emulsions, gels, creams, orsuppositories, including rectal and urethral suppositories.Pharmaceutically acceptable carriers include gums, starches, sugars,cellulosic materials, and mixtures thereof. The pharmaceuticalpreparation containing the SARM agent can be administered to a subjectby, for example, subcutaneous implantation of a pellet; in oneembodiment, the pellet provides for controlled release of SARM agentover a period of time. The preparation can also be administered byintravenous, intraarterial, or intramuscular injection of a liquidpreparation, oral administration of a liquid or solid preparation, or bytopical application. Administration can also be accomplished by use of arectal suppository or a urethral suppository.

[0158] The pharmaceutical preparations of the invention can be preparedby known dissolving, mixing, granulating, or tablet-forming processes.For oral administration, the SARM agents or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like aremixed with additives customary for this purpose, such as vehicles,stabilizers, or inert diluents, and converted by customary methods intosuitable forms for administration, such as tablets, coated tablets, hardor soft gelatin capsules, aqueous, alcoholic or oily solutions. Examplesof suitable inert vehicles are conventional tablet bases such aslactose, sucrose, or cornstarch in combination with binders such asacacia, cornstarch, gelatin, with disintegrating agents such ascornstarch, potato starch, alginic acid, or with a lubricant such asstearic acid or magnesium stearate.

[0159] Examples of suitable oily vehicles or solvents are vegetable oranimal oils such as sunflower oil or fish-liver oil. Preparations can beeffected both as dry and as wet granules. For parenteral administration(subcutaneous, intravenous, intraarterial, or intramuscular injection),the SARM agents or their physiologically tolerated derivatives such assalts, esters, N-oxides, and the like are converted into a solution,suspension, or emulsion, if desired with the substances customary andsuitable for this purpose, for example, solubilizers or otherauxiliaries. Examples are sterile liquids such as water and oils, withor without the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. Illustrative oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil, ormineral oil. In general, water, saline, aqueous dextrose and relatedsugar solutions, and glycols such as propylene glycols or polyethyleneglycol are preferred liquid carriers, particularly for injectablesolutions.

[0160] The preparation of pharmaceutical compositions which contain anactive component is well understood in the art. Typically, suchcompositions are prepared as aerosols of the polypeptide delivered tothe nasopharynx or as injectables, either as liquid solutions orsuspensions; however, solid forms suitable for solution in, orsuspension in, liquid prior to injection can also be prepared. Thepreparation can also be emulsified. The active therapeutic ingredient isoften mixed with excipients which are pharmaceutically acceptable andcompatible with the active ingredient. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol, or the like or anycombination thereof.

[0161] In addition, the composition can contain minor amounts ofauxiliary substances such as wetting or emulsifying agents, pH bufferingagents which enhance the effectiveness of the active ingredient.

[0162] An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the polypeptide or antibody molecule), which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed from the free carboxyl groups can also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

[0163] For topical administration to body surfaces using, for example,creams, gels, drops, and the like, the SARM agents or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like can be prepared and applied as solutions, suspensions, oremulsions in a physiologically acceptable diluent with or without apharmaceutical carrier.

[0164] In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

[0165] For use in medicine, the salts of the SARM may bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid.

[0166] The following examples are presented in order to more fullyillustrate the preferred embodiments of the invention. They should in noway be construed, however, as limiting the broad scope of the invention.

EXPERIMENTAL DETAILS SECTION EXAMPLE 1 Nonsteroidal Ligands withAndrogenic and Anabolic Activity

[0167] The SARM compounds provided herein were designed, synthesized andevaluated for in-vitro and in-vivo pharmacologic activity. The in-vitroandrogen receptor binding affinity and ability to maintain androgendependent tissue growth in castrated animals was studied. Androgenicactivity was monitored as the ability of the SARM compounds to maintainand/or stimulate the growth of the prostate and seminal vesicles, asmeasured by weight. Anabolic activity was monitored as the ability ofthe SARM compounds to maintain and/or stimulate the growth of thelevator ani muscle, as measured by weight.

Synthetic Procedures

[0168] (2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid (R-129).D-Proline (R-128, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOHand cooled in an ice bath; the resulting alkaline solution was dilutedwith acetone (71 mL). An acetone solution (71 mL) of metacrylolychloride 127 (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) weresimultaneously added over 40 min to the aqueous solution of D-proline inan ice bath. The pH of the mixture was kept at 10-11° C. during theaddition of the metacryloly chloride. After stirring (3 h, roomtemperature), the mixture was evaporated in vacuo at a temperature at35-45° C. to remove acetone. The resulting solution was washed withethyl ether and was acidified to pH 2 with concentrated HCl. The acidicmixture was saturated with NaCl and was extracted with EtOAc (100 mL×3).The combined extracts were dried over Na₂SO₄, filtered through Celite,and evaporated in vacuo to give the crude product as a colorless oil.Recrystallization of the oil from ethyl ether and hexanes afforded 16.2(68%) of the desired compound as colorless crystals: mp 102-103° C.(lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compounddemonstrated the existence of two rotamers of the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ5.28 (s) and 5.15 (s) for the first rotamer, 5.15(s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers,vinyl CH₂), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for thesecond rotamer (totally 1H for both rotamers, CH at the chiral canter),3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH₂, CH,Me); ¹³C NMR (75 MHz, DMSO-d₆) δ for major rotamer 173.3, 169.1, 140.9,116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0,141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737(C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm⁻¹; [α]_(D)²⁶+80.80° (c=1, MeOH); Anal. Calcd. for C₉H₁₃NO₃: C 59.00, H 7.15, N7.65. Found: C 59.13, H 7.19, N 7.61.

[0169](3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1c][1,4]oxazine-1,4-dione(R, R-130). A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF wasadded dropwise to a stirred solution of compound R-129 (16.1 g, 88 mmol)in 70 mL of DMF under argon at room temperature, and the resultingmixture was stirred 3 days. The solvent was removed in vacuo, and ayellow solid was precipitated. The solid was suspended in water, stirredovernight at room temperature, filtered, and dried to give 18.6 (81%)(smaller weight when dried ˜34%) of the title compound as a yellowsolid: mp 152-154°0 C. (lit. [214] mp 107-109° C. for the S-isomer); ¹HNMR (300 MHz, DMSO-d₆) δ4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at thechiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d, J=11.4 Hz,1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH), 2.04-1.72(m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ167.3,163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745(C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159, 1062 cm⁻¹;[α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. for C₉H₁₂BrNO₃: C41.24, H 4.61, N 5.34. Found: C 41.46, H 4.64, N 5.32.

[0170] (2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid (R-131). A mixtureof bromolactone R-130 (18.5 g, 71 mmol) in 300 mL of 24% HBr was heatedat reflux for 1 h. The resulting solution was diluted with brine (200mL), and was extracted with ethyl acetate (100 mL×4). The combinedextracts were washed with saturated NaHCO₃ (100 mL×4). The aqueoussolution was acidified with concentrated HCl to pH=1, which, in turn,was extracted with ethyl acetate (100 mL×4). The combined organicsolution was dried over Na₂SO₄, filtered through Celite, and evaporatedin vacuo to dryness. Recrystallization from toluene afforded 10.2 g(86%) of the desired compound as colorless crystals: mp 107-109° C.(lit. [214] mp 109-113° C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆)δ3.63 (d, J=10.1 Hz, 1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)),1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O),1449, 1421, 1380, 1292, 1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.5° (c=2.6, MeOH);Anal. Calcd. for C₄H₇BrO₃: C 26.25, H 3.86. Found: C 26.28, H 3.75.

[0171]N-[4-Nitro-3-(trifluoromethyl)phenyl]-(2R)-3-bromo-2-hydroxy-2-methylpropanamide(R-132). Thionyl chloride (8.6 g, 72 mmol) was added dropwise underargon to a solution of bromoacid R-131 (11.0 g, 60 mmol) in 70 mL of DMAat −5 to −10° C. The resulting mixture was stirred for 2 h under thesame conditions. A solution of 4-nitro-3-trifluoromethyl-aniline (12.4g, 60 mmol) in 80 mL of DMA was added dropwise to the above solution,and the resulting mixture was stirred overnight at room temperature. Thesolvent was removed on Rotavapor using high vacuum oil pump; the residuewas diluted with saturated NaHCO₃ solution, and extracted with ethylether (100 mL×3). Combined extracts were dried over anhydrous Na₂SO₄,filtered through Celite, and purified by flash chromatography on silicagel, using methylene chloride as eluent to afford 18.0 g (80%) of thedesired compound: mp 98-100° C. (R_(f)=0.2, silica gel, CH₂Cl₂); ¹H NMR(300 MHz, DMSO-d₆) δ10.54 (s, 1H, NH), 8.54 (d, J=2.1 Hz, 1H, ArH), 8.34(dd, J=9.0 Hz, J=2.1 Hz, 1H, ArH), 8.18 (d, J=9.0 Hz, 1H, ArH), 6.37 (s,1H, OH), 3.82 (d, J=10.4 Hz, 1H, CHH_(a)), 3.58 (d, J=10.4 Hz, 1H,CHH_(b)), 1.48 (s, 3H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ173.6 (C═O),143.0, 127.2, 123.2, 122.6 (q, J=33.0 Hz), 122.0 (q, J=271.5 Hz), 118.3(q, J=6.0 Hz), 74.4, 41.4,24.9; IR (KBr) 3344 (OH), 1680 (C═O), 1599,1548 (C═C, Ar), 1427, 1363, 1161 cm⁻¹; MS (ESI): m/z 370.8 (M)⁺; Anal.Calcd. for C₁₁H₁₀BrN₂O₄: C 35.60, H 2.72, N 7.55. Found: C 35.68, H2.72, N 7.49.

[0172] N-[4-nitro-3-trifluoromethyl)phenyl]-(2S)-3-[4-(acetylamino) phenoxy]-2-hydroxy-2-methylpropanamide (S-147, Compound V). The titlecompound was prepared from compound R-132 (0.37 g, 1.0 mmol),4-acetamidophenol (0.23 g, 1.5 mmol) K₂CO₃ (0.28 g, 2.0 mmol), and 10%of benzyltributylammonium chloride as a phase transfer catalyst in 20 mLof methyl ethyl ketone was heated at reflux overnight under argon. Thereaction was followed by TLC, the resulting mixture was filtered throughCelite, and concentrated in vacuo to dryness. Purification by flashcolumn chromatography on silica gel (hexanes-ethyl acetate, 3:1) yielded0.38 g (86%) (R_(f)=0.18 hexanes-ethyl acetate, 3:1) of the desiredcompound as a light yellow powder: mp 70-74° C.; The solid can berecrystalized from ethyl acetate and hexane); ¹H NMR (300 MHz, DMSO-d₆)δ10.62 (s, 1H, NH), 9.75 (s, 1H, NH), 8.56 (d, J=1.9 Hz, 1H, ArH), 8.36(dd, J=9.1 Hz, J=1.9 Hz, 1H, ArH), 8.18 (d, J=9.1 Hz, 1H, ArH), 7.45-7.4(m, 2H, ArH), 6.85-6.82 (m, 2H, ArH), 6.25 (s, 1H, OH), 4.17 (d, J=9.5Hz, 1H, CHH_(a)), 3.94 (d, J 9.5 Hz, 1H, CHH_(b)), 1.98 (s, 3H, Me),1.43 (s, 3H, Me); ¹³C NMR (75 MHz, DMSO-d₆) δ174.6 (C═O), 167.7, 154.2,143.3, 141.6, 132.8, 127.4, 123.0, 122.7 (q, J=33.0 Hz), 122.1 (q,J=271.5 Hz), 120.1, 118.3 (q, J=6.0 Hz), 114.6, 74.9, 73.8, 23.8, 23.0;IR (KBr) 3364 (OH), 1668 (C═O), 1599, 1512 (C═C, Ar), 1457, 1415, 1351,1323, 1239, 1150 1046 cm³¹ ¹; MS (ESI): m/z 464.1 (M+Na)⁺; Anal. Calcd.for C₁₉H₁₈F₃N₃O₆: C 51.71, H 4.11, N 9.52. Found: C 52.33, H 4.40, N9.01.

[0173] The synthesis of the various ether analogs of Compound V, suchas, but not limited to, compounds I-IV and VI-VII provided herein,utilizes the common intermediate that is the final reaction step.Bromo-intermediates are used which allow various phenolic compounds todisplace the bromide to give the desired ether product. Bromohydrin wasconverted to an epoxide and to open the epoxide to give the same desiredether product.

[0174] The in-vitro activity of the SARM compounds, specificallycompound V, demonstrated high androgen receptor binding affinity (Ki=7.5nM). Animal studies with the SARM compounds, specifically compound V,demonstrated that it is a potent androgenic and anabolic nonsteroidalagent. Four groups of rats were used for these studies: (1) intactcontrols, (2) castrated controls, (3) castrated animals treated withtestosterone propionate (100 μg/day), and (4) castrated animals treatedwith compound V (1000 μg/day). Testosterone and compound V weredelivered at a constant rate for 14 days via subcutaneous osmotic pumps.

[0175] The results of these studies are shown in FIG. 1. Castrationsignificantly reduced the weight of androgenic (e.g., prostate andseminal vesicles) and anabolic (e.g., levator ani muscle) tissues, buthad little effect on animal body weight (BW). Treatment of castratedanimals with testosterone propionate or compound V maintained the weightof androgenic tissues to the same degree. Compound V had similarandrogenic activity as testosterone propionate (i.e., the prostate andseminal vesicle weights were the same), but much greater efficacy as ananabolic agent. Compound V showed greater anabolic activity thantestosterone propionate at the doses tested (i.e., the levator animuscle maintained the same weight as intact control animals and wasgreater than that observed for testosterone). The experiments presentedherein are the first in-vivo results which demonstrate tissue-selectiveandrogenic and anabolic activity (i.e., differing androgenic andanabolic potency) of a nonsteroidal ligand for the androgen receptor.

EXAMPLE 2 Nonsteroidal Ligands with Androgenic and Anabolic Activity

[0176] The in-vivo efficacy and acute toxicity of four novelnonsteroidal androgens (compounds III, V, VI and VII) in rats wasexamined. In-vitro assays established that these compounds bind theandrogen receptor with very high affinity. The structures and names ofthe four compounds are presented below:

[0177] Compound III R═F

[0178] Compound V R═NHCOCH₃

[0179] Compound VI R═COCH₃

[0180] Compound VII R═COC₂H₅

EXPERIMENTAL METHODS

[0181] Materials. The S-isomers of III, V, VI and VII R-isomer ofcompound III were synthesized in accordance with the scheme as set forthin FIG. 9. Testosterone propionate (TP), polyethylene glycol 300(PEG300, reagent grade) and neutral buffered formalin (10% w/v) werepurchased from Sigma Chemical Company (St Louis, Mo.). Alzet osmoticpumps (model 2002) were purchased from Alza Corp. (Palo Alto, Calif.).

[0182] Animals. Immature male Sprague-Dawley rats, weighing 90 to 100 g,were purchased from Harlan Biosciences (Indianapolis, Ind.). The animalswere maintained on a 12-hour light-dark cycle with food and wateravailable ad libitum. The animal protocol was reviewed and approved bythe Institutional Laboratory Animal Care and Use Committee.

[0183] Study Design. Rats were randomly distributed into twenty-nine(29) groups, with 5 animals per group. Treatment groups are described inTable 1. One day prior to the start of drug treatment, animals in groups2 through 29 were individually removed from the cage, weighed andanesthetized with an intraperitoneal dose of ketamine/xylazine (87/13mg/kg; approximately 1 mL per kg). When appropriately anesthetized(i.e., no response to toe pinch), the animals' ears were marked foridentification purposes. Animals were then placed on a sterile pad andtheir abdomen and scrotum washed with betadine and 70% alcohol. Thetestes were removed via a midline scrotal incision, with sterile suturebeing used to ligate supra-testicular tissue prior to surgical removalof each testis. The surgical wound site was closed with sterilestainless steel wound clips, and the site cleaned with betadine. Theanimals were allowed to recover on a sterile pad (until able to stand)and then returned to their cage.

[0184] Twenty-four hours later, animals in groups 2 through 29 werere-anesthetized with ketamine/xylazine, and an Alzet osmotic pump(s)(model 2002) was placed subcutaneouly in the scapular region. In thisinstance, the scapular region was shaved and cleaned (betadine andalcohol) and a small incision (1 cm) made using a sterile scalpel. Theosmotic pump was inserted and the wound closed with a sterile stainlesssteel wound clip. Animals were allowed to recover and were returned totheir cage. Osmotic pumps contained the appropriate treatment(designated in Table 1) dissolved in polyethylene glycol 300 (PEG300).Osmotic pumps were filled with the appropriate solution one day prior toimplantation. Animals were monitored daily for signs of acute toxicityto drug treatment (e.g., lethargy, rough coat).

[0185] After 14 days of drug treatment, rats were anesthetized withketamine/xylazine. Animals were then sacrificed by exsanguinations underanesthesia. A blood sample was collected by venipuncture of theabdominal aorta, and submitted for complete blood cell analysis. Aportion of the blood was placed in a separate tube, centrifuged at12,000 g for 1 minute, and the plasma layer removed and frozen at −20°C. The ventral prostates, seminal vesicles, levator ani muscle, liver,kidneys, spleen, lungs, and heart were removed, cleared of extraneoustissue, weighed, and placed in vials containing 10% neutral bufferedformalin. Preserved tissues were sent to GTx, Inc. for histopathologicalanalysis.

[0186] For data analysis, the weights of all organs were normalized tobody weight, and analyzed for any statistical significant difference bysingle-factor ANOVA. The weights of prostate and seminal vesicle wereused as indexes for evaluation of androgenic activity, and the levatorani muscle weight was used to evaluate the anabolic activity.

RESULTS

[0187] The androgenic and anabolic activities the S isomers of compoundsIII, V, VI and VII, and the R isomer of compound III were examined in acastrated rat model after 14 days of administration. Testosteronepropionate, at increasing doses, was used as the positive control ofanabolic and androgenic effects.

[0188] As shown in FIGS. 2 and 3, the weights of prostate, seminalvesicle, and levator ani muscle in castrated, vehicle-treated ratsdecreased significantly, due to the ablation of endogenous androgenproduction. Exogenous administration of testosterone propionate, anandrogenic and anabolic steroid, increased the weights of prostate,seminal vesicle, and levator ani muscle in castrated rats in adose-dependent manner. The R-isomer of compound III, and S-isomers ofcompounds VI and VII showed no effect on the weights of prostate,seminal vesicle, and levator ani muscle in castrated animals (data notshown). The S-isomers of compound V (FIG. 2: V) and compound III (FIG.3: III) resulted in dose-dependent increases in prostate, seminalvesicle and levator ani muscle weights. Compared with testosteronepropionate, compound V showed lower potency and intrinsic activity inincreasing the weights of prostate and seminal vesicle, but a greaterpotency and intrinsic activity in increasing the weight of levator animuscle. Particularly, compound V, at a dose as low as 0.3 mg/day, wasable to maintain the levator ani muscle weight of castrated animals inthe same level as that of intact animals. Thus, compound V is a potentnonsteroidal anabolic agent with less androgenic activity but moreanabolic activity than testosterone propionate. This is a significantimprovement over previous claims, in that this compound selectivelystimulates muscle growth and other anabolic effects while having lesseffect on the prostate and seminal vesicles. This may be particularlyrelevant in aging men with concerns related to the development orprogression of prostate cancer.

[0189] Compound III was less potent than compound V, but showed greatertissue selectivity (compare effects on the prostate and seminal vesiclesin FIGS. 2 and 3). Compound III significantly increased levator animuscle weights, but showed little to no ability to stimulate prostateand seminal vesicle growth (i.e., the prostate and seminal vesicleweights were less than 20% of that observed in intact animals or inanimals treated with testosterone propionate).

[0190] Results showed that none of the examined compounds producedsignificant effect on body weight or the weights of other organs (i.e.,liver, kidneys, spleen, lungs and heart). Nor did any compound produceany signs of acute toxicity, as gauged by diagnostic hematology testsand visual examination of animals receiving treatments. Importantly,compound V did not suppress the production of luteinizing hormone (LH)or follicle stimulating hormone (FSH) at a dose of 0.3 mg/day (i.e., adose that exhibited maximal anabolic effects).

[0191] In summary, compound V exhibited exceptional anabolic activity inanimals by maintaining the weight of levator ani muscle after removal ofendogenous androgen. This discovery represents major progress towardsthe development of therapeutically useful nonsteroidal androgens, and amajor improvement (i.e., tissue selectivity and potency) over previousdrugs in this class. Compound III and compound V showed selectiveanabolic activity in comparison with testosterone propionate, anandrogenic and anabolic steroid. The tissue-selective activity isactually one of the advantages of nonsteroidal androgens in terms ofanabolic-related applications.

[0192] Despite similarities in structure and in-vitro functionalactivity, the S-isomers of compounds III and V-VII exhibited profounddifferences in terms of their in-vivo activity. Compound V the mostefficacious androgenic and anabolic activity in animals, with theanabolic activity greater than that of testosterone propionate. CompoundIII showed a small degree of androgenic activity, but an anabolicactivity comparable to testosterone propionate. In contrast, CompoundsVI and VII failed to produce any androgenic or anabolic activityin-vivo.

[0193] These studies show the discovery of two members (III and V) of anew class of selective androgen receptor modulators (SARMS) thatdemonstrate potent anabolic effects (e.g., muscle growth) with lessandrogenic activity (e.g., prostatic growth). This new class of drugshas several advantages over non-selective androgens, including potentialtherapeutic applications in males and females for modulation offertility, erythropoiesis, osteoporosis, sexual libido and in men withor at high risk for prostate cancer.

[0194] Further, FIGS. 7 and 8 demonstrate the effects of compound IIIand compound V on LH and FSH levels in rats. These results furtherdemonstrate the novelty of these SARMs, due to their differentialeffects on these reproductive hormones, thus demonstrating thetissue-specific pharmacologic activity. In FIG. 7, LH levels incastrated animals treated with TP and compound III were significantlylower than those of untreated animals (i.e., castrated controls) atdoses greater than or equal to 0.3 mg/day. However, higher doses (i.e.,0.5 mg/day or higher) of compound V we required before significantdecreases in LH levels were observed. Thus, compound V does not suppressLH levels at doses that are capable of eliciting maximal stimulation oflevator ani muscle growth. In FIG. 8, FSH levels in castrated animalstreated with compound III were significantly lower than those ofuntreated animals (i.e., castrated controls) at doses of 0.5 mg/day orhigher. Similarly, lower FSH levels were observed in animals treatedwith TP. However, only this difference was only significant at a dose of0.75 mg/day. FSH levels in animals treated with compound V were notsignificantly different from those of untreated animals at any doselevel tested. Thus, compound V does not suppress FSH levels at dosesthat are capable of eliciting maximal stimulation of levator ani musclegrowth. TABLE 1 Animals Groups and Experimental Design Group #Castrated? Drug Dose # of animals 1 No None None 5 2 Yes None Vehicleonly 5 3 Yes Testosterone  0.1 mg/day 5 4 Yes Testosterone  0.3 mg/day 55 Yes Testosterone  0.5 mg/day 5 6 Yes Testosterone 0.75 mg/day 5 7 YesTestosterone  1.0 mg/day 5 8 Yes R-III  1.0 mg/day 5 9 Yes S-III  0.1mg/day 5 10 Yes S-III  0.3 mg/day 5 11 Yes S-III  0.5 mg/day 5 12 YesS-III 0.75 mg/day 5 13 Yes S-III  1.0 mg/day 5 14 Yes S-VI  0.1 mg/day 515 Yes S-VI  0.3 mg/day 5 16 Yes S-VI  0.5 mg/day 5 17 Yes S-VI 0.75mg/day 5 18 Yes S-VI  1.0 mg/day 5 19 Yes S-VII  0.1 mg/day 5 20 YesS-VII  0.3 mg/day 5 21 Yes S-VII  0.5 mg/day 5 22 Yes S-VII 0.75 mg/day5 23 Yes S-VII  1.0 mg/day 5 24 Yes S-V  0.1 mg/day 5 25 Yes S-V  0.3mg/day 5 26 Yes S-V  0.5 mg/day 5 27 Yes S-V 0.75 mg/day 5 28 Yes S-V 1.0 mg/day 5 29 Yes None Vehicle only 5

EXAMPLE 3 Pharmacokinetics of Compound V in Dogs

[0195] The pharmacokinetics of S-compound V, a novel selective androgenreceptor modulator (SARM), were characterized in beagle dogs. Afour-treatment, four-period crossover design was utilized in the study,which involved a total of six beagle dogs, three of each gender. Eachanimal received a 3 mg/kg IV dose, a 10 mg/kg IV dose, a 10 mg/kg POdose in solution, and a 10 mg/kg PO dose in capsule, in a randomlyassigned order. There was a one-week washout period between treatments.Plasma samples were collected for up to 72 hr after drug administration.Plasma Compound Vconcentrations were analyzed by a validated HPLCmethod. The clearance (CL), volume of distribution (Vss), half-life(T_(1/2)), and other pharmacokinetic parameters were determined bynoncompartmental methods. Results showed that Compound Vwas cleared fromdog plasma with a terminal T_(1/2) of about 4 hr and a CL of 4.4mL/min/kg after IV administration. FIGS. 4, 5, and 6 show the plasmaconcentration-time profiles of Compound Vafter administration of anintravenous solution, oral solution, and oral capsule, respectively. Thepharmacokinetics were dose- and gender-independent. The oralbioavailability of Compound Vvaried with the dosage form, and averaged38% and 19% for solution and capsule, respectively. Thus, CompoundVdemonstrated moderate half-life, slow clearance and moderatebioavailability in beagle dogs, identifying it as the first of a newclass of orally bioavailable tissue-selective androgen receptormodulators.

EXAMPLE 4 Compound V Analysis by HPLC

[0196] A reversed phase high pressure liquid chromatograph (HPLC) assaywas developed to quantitate Compound V concentrations in dog plasma. Dogblood samples were obtained by venipuncture and centrifuged at 1000 gfor 15 minutes. Samples were stored frozen at −20° C. until analysis.Individual samples were rapidly thawed and an aliquot (0.5 ml) wasspiked with internal standard (20 μl of a 200 μg/ml aqueous solution ofCM-II-87). An aliquot of 1 ml of acetonitrile was added to the samplesto precipitate plasma proteins. The samples were vortexed and thencentrifuged at 1000 g for 15 minutes. The supernatant was decanted intoglass extraction tubes and 7.5 ml of ethyl acetate was added. Theextraction mixture was left at room temperature for 20 minutes, andvortexed several times during this interval. The samples were thencentrifuged at 1000 g for 10 minutes, and the organic phase was removedand placed in conical-bottomed glass tubes. The organic phase wasevaporated under nitrogen. The samples were reconstituted in 200 μl ofmobile phase (35:65 acetonitrile:water) and transferred to anautosampler vial for HPLC injection (Waters 717 plus autosampler, WatersCorp., Milford, Me.). The isocratic mobile phase of 35% (v/v)acetonitrile in water was pumped at a flow rate of 1 ml/min (Model 510,Waters Corp.). The stationary phase was a C18 reversed phase column(Novapak C18, 3.9×150 mm). Analytes were monitored with UV detection at270 nm (Model 486 absorbance detector, Waters Corp.). Retention timesfor Compound V and CM-II-87 were 11.1 and 16.9 minutes, respectively.Chromatography data was collected and analyzed using Millenniumsoftware. Plasma concentrations of Compound V in each sample weredetermined by comparison to calibration curves. Calibration curves wereconstructed by adding known amounts of Compound V to dog plasma. FinalCompound V concentrations in dog plasma samples used in the calibrationcurves were 0.08, 0.2, 0.4, 2, 4, 10, and 20 μg/ml. Calibration curveswere linear over this concentration range and exhibited correlationcoefficients (r2) of 0.9935 or greater. Intra- and inter-daycoefficients of variation for the standards ranged from 6.4% for 0.08μg/ml to 7.9% for 20 μg/ml.

[0197] Melting points were determined on a Thomas-Hoover capillarymelting point apparatus and are uncorrected. Infrared spectra wererecorded on a Perkin Elmer System 2000 FT-IR. Optical rotations weredetermined on an Autopol® III Automatic Polarimeter (Rudolph ResearchModel III-589-10, Fairfield, N.J.). Proton and carbon-13 magneticresonance spectra were obtained on a Bruker AX 300 spectrometer (300 and75 MHz for ¹H and ¹³C, respectively). Chemical shift values werereported as parts per million (δ) relative to tetramethylsilane (TMS).Spectral data were consistent with assigned structures. Mass spectrawere determined on a Bruker-HP Esquire LC System. Elemental analyseswere performed by Atlantic Microlab Inc. (Norcross, Ga.), and foundvalues were within 0.4% of the theoretical values. Routine thin-layerchromatography (TLC) was performed on silica gel on aluminum plates(silica gel 60 F 254, 20×20 cm, Aldrich Chemical Company Inc.,Milwaukee, Wis.). Flash chromatography was performed on silica gel(Merck, grade 60, 230-400 mesh, 60). Tetrahydrofuran (THF) was dried bydistillation over sodium metal. Acetonitrile (MeCN) and methylenechloride (CH₂Cl₂) were dried by distillation from P₂O₅.

[0198] It will be appreciated by a person skilled in the art that thepresent invention is not limited by what has been particularly shown anddescribed hereinabove. Rather, the scope of the invention is defined bythe claims that follow:

What is claimed is:
 1. A selective androgen receptor modulator (SARM)compound having in-vivo androgenic and anabolic activity of anonsteroidal ligand for the androgen receptor, said compound representedby the structure of formula I:

wherein X is O, CH₂, NH, Se, PR, NO or NR; T is OH, OR, —NHCOCH₃, orNHCOR; Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl,CN, CR₃ or SnR₃; Q is F, Cl, Br or I; R is alkyl, haloalkyl,dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃, CF₂CF₃, aryl, phenyl,halogen, alkenyl or OH; and R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, orCF₂CF₃.
 2. A selective androgen receptor modulator (SARM) compoundrepresented by the structure of formula I:

wherein X is O, CH₂, NH, Se, PR, NO or NR; T is OH, OR, —NHCOCH₃, orNHCOR; Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl,CN, CR₃ or SnR₃; Q is F, Cl, Br or I; R is alkyl, haloalkyl,dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃, CF₂CF₃, aryl, phenyl,halogen, alkenyl or OH; and R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, orCF₂CF₃; or its analog, isomer, metabolite, derivative, pharmaceuticallyacceptable salt, pharmaceutical product, N-oxide, hydrate or anycombination thereof.
 3. The compound according to claim 1, wherein X isO.
 4. The compound according to claim 1, wherein Z is NO₂.
 5. Thecompound according to claim 1, wherein Z is CN.
 6. The compoundaccording to claim 1, wherein Y is CF₃.
 7. The compound according toclaim 1, wherein Q is F.
 8. The compound according to claim 1, wherein Tis OH.
 9. The compound according to claim 1, wherein R₁ is CH₃.
 10. Thecompound according to claim 1, wherein X is O; Z is NO₂; Y is CF₃; Q isF; T is OH; and R₁ is CH₃.
 11. The compound according to claim 1,wherein X is O; Z is CN; Y is CF₃; Q is F; T is OH; and R₁ is CH₃. 12.The compound according to claim 1, wherein Q is in the para position.13. The compound according to claim 1, whereinZ is in the para position.14. The compound according to claim 1, wherein Y is in the metaposition.
 15. The compound according to claim 1, represented by thestructure of formula II:


16. The compound according to claim 1, represented by the structure offormula III:


17. The compound according to claim 1, represented by the structure offormula IV:


18. A composition comprising the selective androgen receptor modulatorcompound of claim 1 and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof; and a suitable carrier or diluent.19. A pharmaceutical composition comprising an effective amount of theselective androgen receptor modulator compound of claim 1 and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate or N-oxide or any combinationthereof; and a pharmaceutically acceptable carrier, diluent or salt. 20.A method of binding a selective androgen receptor modulator compound toan androgen receptor, comprising the step of contacting the androgenreceptor with the selective androgen receptor modulator compound ofclaim 1 and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to bind theselective androgen receptor modulator compound to the androgen receptor.21. A method of suppressing spermatogenesis in a subject comprisingcontacting an androgen receptor of the subject with the selectiveandrogen receptor modulator compound of claim 1 and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to suppress sperm production.
 22. A method ofcontraception in a male subject, comprising the step of administering tosaid subject the selective androgen receptor modulator compound of claim1 and/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to suppress sperm productionin said subject, thereby effecting contraception in said subject.
 23. Amethod of hormone therapy comprising the step of contacting an androgenreceptor of a subject with the selective androgen receptor modulatorcompound of claim 1 and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to effect achange in an androgen-dependent condition.
 24. A method of hormonereplacement therapy comprising the step of contacting an androgenreceptor of a subject with the selective androgen receptor modulatorcompound of claim 1 and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to effect achange in an androgen-dependent condition.
 25. A method of treating asubject having a hormone related condition, comprising the step ofadministering to said subject the selective androgen receptor modulatorcompound of claim 1 and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to effect achange in an androgen-dependent condition.
 26. A method of treating asubject suffering from prostate cancer, comprising the step ofadministering to said subject the selective androgen receptor modulatorcompound of claim 1 and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate orN-oxide or any combination thereof, in an amount effective to treatprostate cancer in said subject.
 27. A method of preventing prostatecancer in a subject, comprising the step of administering to saidsubject the selective androgen receptor modulator compound of claim 1and/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to prevent prostate cancerin said subject.
 28. A method of delaying the progression of prostatecancer in a subject suffering from prostate cancer, comprising the stepof administering to said subject the selective androgen receptormodulator compound of claim 1 and/or its analog, derivative, isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate or N-oxide or any combination thereof, in an amount effective todelay the progression of prostate cancer in said subject.
 29. A methodof preventing the recurrence of prostate cancer in a subject sufferingfrom prostate cancer, comprising the step of administering to saidsubject the selective androgen receptor modulator compound of claim 1and/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to prevent the recurrence ofprostate cancer in said subject.
 30. A method of treating the recurrenceof prostate cancer in a subject suffering from prostate cancer,comprising the step of administering to said subject the selectiveandrogen receptor modulator compound of claim 1 and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to treat the recurrence of prostate cancer insaid subject.
 31. A method of treating a dry eye condition in a subjectsuffering from dry eyes, comprising the step of administering to saidsubject the selective androgen receptor modulator compound of claim 1and/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate or N-oxide or anycombination thereof, in an amount effective to treat dry eyes in thesubject.
 32. A method of preventing a dry eye condition in a subject,comprising the step of administering to said subject the selectiveandrogen receptor modulator compound of claim 1 and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate or N-oxide or any combination thereof,in an amount effective to prevent dry eyes in the subject.